1. Field of the Invention
The present invention relates to a gelatin-based nanoparticle complex for tumor-targeted delivery of siRNA for specific gene silencing in tumor cells and a method for preparing the same.
2. Description of the Related Art
RNA interference (RNAi), a conserved mechanism for gene silencing, is a powerful therapeutic tool for treating various diseases including cancer. However, clinical application of small interfering RNA (siRNA) for RNAi is limited by the poor stability and inefficient cellular uptake of siRNA. The major challenge in siRNA therapy is to improve the efficiency of siRNA delivery.
Various carriers have been developed to effectively deliver siRNA. In general, strong cationic polymer-based nanoparticles have been widely considered as siRNA carriers. Although the cationic polymers showed high affinity for siRNA molecules to form nanoparticles through electrostatic interaction, the resulting nanoparticles usually have considerable toxicity and immunogenicity. Moreover, the cationic polymer-based vector systems commonly showed low target specificity in vivo that limited their clinical applications.
Recently, various structural modifications of siRNA molecules have attempted to overcome the inherent problems of siRNA delivery. Indeed, prudent modifications of the siRNA backbone improved its physiochemical properties for being incorporated in gene carriers without loss of gene-silencing efficacy. Modified siRNA, such as sticky siRNA and chemically modified polymerized siRNA (poly-siRNA), formed siRNA polymers through complementary A5-8/T5-8 3′ overhangs and chemical self-cross-linking. Compared to natural siRNA, the modified siRNA polymers showed enhanced delivery efficiency by forming condensed nanoparticles with various polymeric carriers, based on the higher molecular weight and increased charge density. Thus, the structurally modified siRNAs provide a wider variety of choice of vector systems for siRNA delivery, because these siRNAs show a higher binding affinity for carriers.
Proteins generally show low toxicity and high binding affinity for various drugs. The aqueous steric barrier of protein-based carriers allows low levels of reticuloendothelial system (RES) clearance, leading to improved pharmacokinetic properties. From this perspective, natural proteins are attractive materials as a potential gene carrier to achieve safe and efficient gene delivery. In particular, gelatin is a competitive candidate as a siRNA carrier. Gelatin can be simply modified with numerous functional groups, and it shows low cytotoxicity and antigenicity as a denatured form of collagen. Moreover, gelatin has great potential for in vivo application. The gelatin injection is commonly administered subcutaneously, but it can also be intravenously injected for a specific therapeutic purpose. In practice, Gelafundin and Gelafusal, which consist of gelatin derivates, are intravenously administered in the clinical setting. However, natural gelatin has not been used as a siRNA carrier because the loose complexes of gelatin and natural siRNA can be easily degraded in the bloodstream before RNAi performance.